Hyperpolarization-activated Cyclic Nucleotide gated (HCN) were identified in the late 1970s and early 1980s in sinoatrial node cells and neurons, respectively (Brown et al., 1979; halliwell and Adams, 1982). HCN channels are members of the pore loop cation channels superfamily (yu et al., 2005). In mammals the HCN channel family includes 4 members (HCN1-4) that are differentially expressed in different types of excitable tissues (for review see: Biel et al., 2009; Kaup and Seifert, 2001) and share approximately 60% sequence identity with each other and are present in all vertebrates (Ludwig et al., 1998). HCN channels form tetrameric complexes consisting of homomeric or heteromeric subunit compositions with each subunit consisting of six transmembrane alpha helices. Similar to other voltage-gated channels, HCN channels possess voltage sensors (Manniko et al., 2002). HCN channels are activated by membrane hyperpolarization and upon opening give rise to a depolarizing mixed cation current termed Ih, If or Iq, which cause the re-depolarization of the membrane potential to near resting potentials. HCN channels contain a cyclic nucleotide binding domain in the carboxyl terminus. Following the binding of cyclic AMP or cyclic GMP, the activation kinetics of the channels are shifted to become more sensitive to membrane hyperpolarization (Wainger et al., 2001). Aside from their role as pacemakers in the sino-atrial node of the heart, HCN channels perform important functions in neuronal cells including determination of resting membrane potential, dendritic integration, action potential rhythmicity, synaptic transmission and synaptic plasticity (for review see: Robinson and Siegelbaum, 2003).
Different HCN channel subtypes are expressed throughout the central nervous system (Biel et al., 2009) including the retina where all isoforms are expressed, with HCN1 and HCN4 showing dominant expression (Muller et al., 2003). HCN1 is expressed in all major retinal neuronal subtypes whereas HCN4 is expressed predominantly in bipolar and ganglion cell (Stradleigh et al., 2011). Targeted deletion of HCN1 from the mouse retina results in prolonged light responses as seen in electroretinogram flicker responses suggesting an important function of these channels in rod and cone photoreceptors since B-wave amplitude, which result from ON-bipolar cell function, remained unaltered, or slightly reduced in these animals (Knop et al., 2008). Both HCN1 and HCN4 are expressed in retinal ganglion cells where most cells show a mosaic of expression pattern (Stradleigh et al., 2011). Although strongly expressed in ganglion cells, the function of these channels in ganglion cells and overall visual physiology is unclear.
WO2011000915A1 refers to isoform-selective HCN blockers.
U.S. Pat. No. 8,076,325 B2 refers to 1,2,4,5-tetrahydro-3H-benzazepine compounds as blockers of HCN channels, a process for their preparation and pharmaceutical compositions containing them.
WO 2008/121735 refers to methods of identifying modulators of HCN channels.